Methods for synthesizing 3-(Substituted Dihydroisoindolinone-2-YI)-2, 6-Dioxopiperidine, and intermediates thereof

ABSTRACT

The present invention discloses methods for synthesizing 3-(substituted dihydroisoindolinone-2-yl)-2,6-dioxopiperidine and intermediates thereof, namely, the synthesis of compounds of the Formula (I), with each substitutional group defined in the patent specification. Owing to the advantages of high productivity, little influence to the environment and material accessibility, the methods of the present invention is suitable for industrial production.

TECHNICAL FIELD

The present invention is in the field of pharmaceutical chemistry, andmore specifically it relates to methods for synthesizing 3-(substituteddihydroisoindolinone-2-yl)-2,6-dioxopiperidine, and intermediatesthereof.

BACKGROUND ART

Lenalidomide, an analog of Thalidomide, is a kind of immunomodulatorwith anti-vascular proliferation and anti-tumor activities; its chemicalname is3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine andits chemical structure is as following:

Lenalidomide has the residue of dioxopiperidine and dihydroisoindolineresidue, as well as an asymmetric center in its structure. At presentLenalidomide approved on the market are racemic mixtures.

As is manifest in the article “Amino-substituted thalidomide analogs:Potent inhibitors of TNF-α production” (Bioorganic & Medicinal ChemistryLetters, Vol. 9, Issue 11, 7 Jun., 1999, pp 1625-1630) and the ChinesePatent ZL97180299.8 by Muller etc., the method of preparing3-(substituted dihydroisoindolinone-2-yl)-2,6-dioxopiperidine is asfollowing: α-aminoglutarimide hydrochloride reacts with methyl2-bromomethyl-3-nitrobenzoate, then hydrogenated over Pd/C to yieldlenalidomide.

wherein, (a) under ultraviolet light (mercury lamp), NBS, CCL₄,refluxing; (b) Et₃N, DMF, 80° C.; (c) H₂, 10% Pd/C, MeOH. 7a X=4-NO₂, 8aX=4-NH₂. In which, the synthesis of α-aminoglutarimide hydrochloridebegins with N-benzyloxycarbony-L-glutamine which reacts withN,N′-carbonyldiimidazole (CDI) refluxing in THF to yieldN-benzyloxycarbony-aminoglutarimide; the key material of the reactionis: methyl 2-bromomethyl-3-nitro benzoate, which is converted from2-methyl-3-nitrobenzoate by catalytic bromination in the condition ofcarbon tetrachloride under ultraviolet light. The catalytic andrefluxing reaction needs long time and the yield is low. Additionally,the mass production is unease to be realized due to the difficulty ofworkers' labour protection against ultraviolet produced by mercury lampas catalytic light source.

In the US Patent application US2006/0052609 A1, Muller etc. disclosedanother synthetic method of 3-(substituteddihydroisoindolinone-2-yl)-2,6-dioxopiperidine:

In the US Patent application US2006052609A1 and the Chinese Patentapplication CN97180299.8, the reaction product was purified by columnchromatography at least twice or more, which made industrial operationcomplicated and made it difficult to industrial scale-up production.

In the US Patent application US2006052609A1 and the Chinese Patentapplication CN97180299.8, pressurized hydrogenation was both utilizedtwice, which was of much more risk in industrial operation.

In addition, when N-benzyloxycarbony-L-glutamine, as initial material,reacted with N,N′-carbonyldiimidazole in THF refluxing for 24 h to yieldN-benzyloxycarbony-aminoglutarimide, low purity of yield due to longreactive time for refluxing and high temperature made extractiondifficult.

On the other hand, the total yield was lower than 20% and 18%respectively reported in the US Patent application US2006052609A1 andthe Chinese Patent application. Also, in the above two documents “lethalcarbon tetrachloride” was reported to be reactive solvent used forrefluxing. Carbon tetrachloride had serious destruction to ozone layer,which was forbidden to use by UNEP. Because of the high toxicity ofcarbon tetrachloride, it was difficult to dispose this substance, whichis harmful to environment.

SUMMARY OF INVENTION

The present invention provides a novel method for synthesizing3-(substituted dihydroisoindolinone-2-yl)-2,6-dioxopiperidine and itsintermediates, which overcame the disadvantages mentioned above in priorart.

One objective of the present invention is to provide a novel method forsynthesizing 3-(substituteddihydroisoindolinone-2-yl)-2,6-dioxopiperidine.

Another objective of the present invention is to provide theintermediates used to synthesize 3-(substituteddihydroisoindolinone-2-yl)-2,6-dioxopiperidine.

DETAILED DESCRIPTION OF INVENTION

In one embodiment of the present invention, a novel method forsynthesizing the compound of Formula (I) is provided.

Including the reaction of the compound of Formula (II) and the compoundof Formula (III) to yield the compound of Formula (IV);

wherein:

One of R, R3, R4 and R5 is amino or protected amino (carbamates: such ascarbobenzyloxy, t-butyloxycarbonyl, fluorenylmethoxycarbonyl, etc.; acylamides: such as acetyl, phenylacetyl, phthalyl, etc.; azanes: such asallyl, etc.; sulfonyl and sulfinyl: such as phenylsulfonyl,p-toluenesulfonyl, phenylsulfinyl, O-nitrophenylsulfinyl, etc.; referredto Greene T. W. and WuTs P. G. M. Protective Groups in OrganicSynthesis: P494-; East China University Of Science And Technology Press,which is hereby incorporated by reference in their entirety), nitro orhalo (for example F, Cl, Br or I), and the others are all hydrogen,preferably, R3, R4 and R5 are hydrogen;

X is halo, such as: F, Cl, Br or I;

Y is ═O or H;

Z is ═O or H; with the proviso that Y and Z are both ═O; or one of Y andZ is ═O and the other of Y and Z is H;

R′ is alkali metal ion or hydrogen (such as: H, Li⁺, Na⁺, K⁺ or Cs⁺), orimine protecting group (such as ethoxycarbonyl, etc.; referred to GreeneT. W. and WuTs P. G. M. Protective Groups in Organic Synthesis: P494-,East China University Of Science And Technology Press, and ChemicalResearch and Application: 2006, 18(11): 1349-1352), etc., preferably K⁺or Cs⁺, and more preferably Cs⁺;

A and B are each independently hydroxyl, C₁₋₁₀ alkoxy, aryloxy, arylC₁₋₄ alkoxy or NHR₂, and herein, R₂ is hydrogen or amino protectinggroup (carbamates: such as carbobenzyloxy, t-butyloxycarbonyl,fluorenylmethoxycarbonyl, etc.; acyl amides: such as acetyl,phenylacetyl, phthalyl, etc.; azanes: such as allyl, etc.; sulfonyl andsulfinyl: such as phenylsulfonyl, p-toluenesulfonyl, phenylsulfiny,O-nitrophenylsulfinyl, etc.; referred to Protective Groups in OrganicSynthesis: Greene T. W., WuTs P. G. M. East China University Of ScienceAnd Technology Press: P494-); preferably, A and B are each independentlyhydroxyl, methoxyl, ethoxyl, propoxy, isopropoxy, butoxy, isobutoxy,t-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy;phenoxy or substituted phenoxy; phenyl C₁₋₄ alkoxy, such as benzyloxy,phenylethoxy, phenylpropoxy, etc., or substituted phenyl C₁₋₄ alkoxy; interms of the substituted phenoxy or substituted phenyl C₁₋₄ alkoxy, thenumber of the substituted groups is one or more; the substituted groupsare selected from the group consisting of C₁₋₄ alkyl, halo, cyano, andnitro, and the substituted groups may be the same or different,optionally, the groups are substituted at 2, 3, 4, 5 or 6-position ofthe benzene ring, for example 4-nitrobenzyloxyl,2-chloro-4-nitrobenzyloxyl; amino, or benzylamino;

R1 is C₁₋₄ alkyl or hydrogen; the said C₁₋₄ alkyl is selected frommethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl; preferably,R1 is hydrogen or methyl.

The present invention provides the method of synthesizing the compoundof Formula (I) mentioned above, after yielding the compound of Formula(IV), further including that if A and B are both NHR₂, the compound ofFormula (IV) is heated and cyclized in or out of the presence offormamide or methanesulfonic acid to yield the compound of Formula (I);and with the proviso that when R₂ is not hydrogen, the compound ofFormula (IV) undergoes deprotection of amino groups and then cyclizationmentioned above to yield the compound of Formula (I);

when one of A and B is NHR₂ and the other is hydroxyl, the compound ofFormula (IV) reacts in the presence of condensing agent (such as thionylchloride, dicyclohexylcarbodiimide (DCC), phosphorus oxychloride,carbonyldiimidazole, etc.), to yield the compound of Formula (I); andwith proviso that when R₂ is not hydrogen, the compound of Formula (IV)undergoes deprotection of amino groups and then cyclization mentionedabove to yield the compound of Formula (I);

when one of A and B is NHR₂ and the other is C₁₋₁₀ alkoxy, aryloxy, oraryl C₁₋₄ alkoxy, the compound of Formula (IV) is cyclized in alkalinecondition (such as in the presence of inorganic base, for examplepotassium carbonate, sodium carbonate, or organic base, for examplepotassium tert-butoxide or sodium methoxide, etc.), to yield thecompound of Formula (I); and with the proviso that when R₂ is nothydrogen, the compound of Formula (IV) undergoes deprotection of aminogroups and then cyclization mentioned above to yield the compound ofFormula (I);

when A and B are both hydroxyl, the compound of Formula (IV) is cyclizedin the presence of urea, or in the presence of trifluoroacetamide,1-hydroxy benzotriazole (HOBT) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl), to yield the compound of Formula (I);

when A and B are both C₁₋₁₀ alkoxy, aryloxy or aryl C₁₋₄alkoxy, thecompound of Formula (IV) is cyclized in the presence of alkali metalamide (such as lithium amide, sodium amide, potassamide, preferredsodium amide), to yield the compound of Formula (I);

when one of A and B is hydroxyl and the other is C₁₋₁₀ alkoxy, aryloxyor aryl C₁₋₄ alkoxy, the compound of Formula (IV) is firstly esterified,and then cyclized in the presence of alkali metal amide (such as lithiumamide, sodium amide, potassamide, preferred sodium amide), to yield thecompound of Formula (I); alternatively, the compound of Formula (IV) isfirstly ester hydrolyzed, and then cyclized in the presence of urea, orin the presence of trifluoroacetamide, 1-hydroxy benzotriazole (HOBT)and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl),to yield the compound of Formula (I); alternatively, the compound ofFormula (IV) is firstly ammonolyzed and then reacts in the presence ofcondensing agent (such as thionyl chloride, dicyclohexylcarbodiimide(DCC), phosphorus oxychloride, carbonyldiimidazole, etc.), to yield thecompound of Formula (I); alternatively, the compound of Formula (IV) isfirstly acylated, converting its hydroxyl to amino, and then cyclized inalkaline condition (such as in the presence of inorganic base, forexample potassium carbonate, sodium carbonate, etc., or organic base,for example potassium tert-butoxide or sodium methoxide, etc.), to yieldthe compound of Formula (I);

wherein, each substituted group in the Formula (IV) or (I) is defined asabove.

Optionally, the above-mentioned method for synthesizing the compound ofFormula (I) provided by the invention includes that, after yielding thecompound of Formula (IV), when A and B are both C₁₋₁₀ alkoxy, aryloxy,or aryl C₁₋₄ alkoxy, the compound of Formula (IV) is ammonolyzed toyield the monoamide compound of Formula (IV′), and then the monoamidecompound of Formula (IV′) is cyclized in alkaline condition (such as inthe presence of inorganic base, for example potassium carbonate, sodiumcarbonate, etc., or organic base, for example potassium tert-butoxide orsodium methoxide, etc.), to yield the compound of Formula (I); themonoamide compound of Formula (IV′) may alternatively continue to beammonolysed to yield eventually diamide of Formula (IV″), and thendiamide of Formula (IV″) is heated to be cyclized in or out of thepresence of formamide or methanesulfonic acid to yield the compound ofFormula (I);

wherein, each substituted group in the Formula (IV), (IV′), (IV″) and(I) is defined as above.

Optionally, the above-mentioned method for synthesizing the compound ofFormula (I) provided by the invention, after yielding the compound ofFormula (IV), when A and B are both C₁₋₁₀ alkoxy, aryloxy, orarylC₁₋₄alkoxy, further includes that the compound of Formula (IV) ishydrolyzed to yield the monoamide compound of Formula (V);

wherein, each substituted group in the Formula (IV) and (V) is definedas above.

The above-mentioned method for synthesizing the compound of Formula (I)provided by the present invention, after yielding the compound ofFormula (V), further includes that the compound of Formula (V) iscyclized (such as in the condition of acid anhydride and heating) toyield the compound of Formula (VI);

wherein, each substituted group in the Formula (V) and (VI) is definedas above.

The above-mentioned method for synthesizing the compound of Formula (I)provided by the present invention, after yielding the compound ofFormula (VI), further includes that the compound of Formula (VI) isring-opening ammonolyzed to yield the compound of Formula (VII); thenthe compound of Formula (VII) reacts in the presence of condensing agent(such as thionylchloride, dicyclohexylcarbodiimide (DCC), phosphorusoxychloride, carbonyldiimidazole, etc.), to yield the compound ofFormula (I):

wherein, each substituted group in the Formula (VI) and (VII) is definedas above.

The present invention provided a novel method for synthesizing thecompound of Formula (I), which includes the following steps:

(1) the compound of Formula (II) reacts with the compound of Formula(III) in the alkaline condition (such as in the presence of inorganicbase, for example potassium hydroxide, potassium carbonate, sodiumhydroxide, sodium carbonate, cesium hydroxide or cesium carbonate, etc.,otherwise organic base, for example potassium tert-butoxide or sodiummethoxide, etc.), to yield the compound of Formula (IV);

(2) when A and B are both NHR₂, the compound of Formula (IV) is heatedand cyclized in or out of the presence of formamide or methanesulfonicacid to yield the compound of Formula (I); and with the proviso thatwhen R₂ is not hydrogen, the compound of Formula (IV) undergoesdeprotection of amino groups and then cyclization mentioned above toyield the compound of Formula (I);

when one of A and B is NHR₂ and the other is hydroxyl, the compound ofFormula (IV) reacts in the presence of condensing agent (such as thionylchloride, dicyclohexylcarbodiimide (DCC), phosphorus oxychloride,carbonyldiimidazole, etc.), to yield the compound of Formula (I); andwith the proviso that when R₂ is not hydrogen, the compound of Formula(IV) undergoes deprotection of amino groups and then cyclizationmentioned above to yield the compound of Formula (I);

when one of A and B is NHR₂ and the other is C₁₋₁₀ alkoxy, aryloxy, oraryl C₁₋₄alkoxy, the compound of Formula (IV) is cyclized in alkalinecondition (such as in the presence of inorganic base, for examplepotassium carbonate, sodium carbonate, etc., or organic base, forexample potassium tert-butoxide or sodium methoxide, etc.), to yield thecompound of Formula (I); and with the proviso that if R₂ is nothydrogen, the compound of Formula (IV) undergoes deprotection of aminogroups and then cyclization mentioned above to yield the compound ofFormula (I);

when A and B are both hydroxyl, the compound of Formula (IV) is cyclizedin the presence of urea, or in the presence of trifluoroacetamide,1-hydroxy benzotriazole (HOBT) andN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl), toyield the compound of Formula (I);

when A and B are both C₁₋₁₀ alkoxy, aryloxy or aryl C₁₋₄alkoxy, thecompound of Formula (IV) is cyclized in the presence of alkali metalamide (such as lithium amide, sodium amide, potassamide, preferredsodium amide), to yield the compound of Formula (I);

when one of A and B is hydroxyl and the other is C₁₋₁₀ alkoxy, aryloxyor aryl C₁₋₄ alkoxy, the compound of Formula (IV) is firstly esterified,and then cyclized in the presence of alkali metal amide (such as lithiumamide, sodium amide, potassamide, preferred sodium amide), to yield thecompound of Formula (I); alternatively, the compound of Formula (IV) isfirstly ester hydrolyzed, and then cyclized in the presence of urea, orin the presence of trifluoroacetamide, 1-hydroxybenzotriazole (HOBT) andN-ethyl-N′-(3-dimethylamino propyl)-carbodiimide hydrochloride (EDCl),to yield the compound of Formula (I); alternatively, the compound ofFormula (IV) is firstly ammonolyzed and then reacts in the presence ofcondensing agent (such as thionyl chloride dicyclohexylcarbodiimide(DCC), phosphorus oxychloride, carbonyldiimidazole, etc.), to yield thecompound of Formula (I); alternatively, the compound of Formula (IV) isfirstly acylated, converting hydroxyl to amino, and then cyclized inalkaline condition (such as in the presence of inorganic base, forexample potassium carbonate, sodium carbonate, etc., or organic base,for example potassium tert-butoxide or sodium methoxide, etc.), to yieldthe compound of Formula (I).

wherein, each substituted group in the compounds of Formula from (I) to(IV) mentioned above is defined as:

one of R, R3, R4 and R5 is amino or protected amino (carbamates: such ascarbobenzyloxy, t-butyloxycarbonyl, fluorenylmethoxycarbonyl, etc.; acylamides: such as acetyl, phenylacetyl, phthalyl, etc.; azanes: such asallyl, etc.; sulfonyl and sulfinyl: such as phenylsulfonyl,p-toluenesulfonyl, phenylsulfiny, O-nitrophenylsulfinyl, etc.; referredto Greene T. W. and WuTs P. G. M. Protective Groups in OrganicSynthesis: P494-; East China University Of Science And TechnologyPress), nitro or halo (for example F, Cl, Br or I), and the others arehydrogen, preferably, R3, R4 and R5 are hydrogen;

X is halo, such as: F, Cl, Br or I;

Y is ═O or H;

Z is ═O or H; and with the proviso that Y and Z are both ═O; or one of Yand Z is ═O and the other is H;

R′ is alkali metal ion or hydrogen, such as: H; Li⁺; Na⁺; K⁺; Cs⁺; orimine group (such as ethoxycarbonyl, etc.; referred to Greene T. W. andWuTs P. G. M. Protective Groups in Organic Synthesis: P494-, East ChinaUniversity Of Science And Technology Press, and referred to ChemicalResearch and Application: 2006, 18(11): 1349-1352), etc. preferably K⁺or Cs⁺, and more preferably Cs⁺;

A and B are each independently hydroxyl, C₁₋₁₀ alkoxy, aryloxy, arylC₁₋₄ alkoxy or NHR₂ in which R₂ is hydrogen or amino protecting group(carbamates: such as carbobenzyloxy, t-butyloxycarbonyl,fluorenylmethoxycarbonyl, etc.; acyl amides: such as acetyl,phenylacetyl, phthalyl, etc.; azanes: such as allyl, etc.; sulfonyl andsulfinyl: such as phenylsulfonyl, p-toluenesulfonyl, phenylsulfiny,O-nitrophenylsulfinyl, etc.; referred to Protective Groups in OrganicSynthesis: Greene T. W., WuTs P. G. M. East China University Of ScienceAnd Technology Press: P494-); preferably, A and B are each independentlyhydroxyl, methoxy, ethoxyl, propoxy, isopropoxy, butoxy, isobutoxy,t-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy;phenoxy or substituted phenoxy; phenyl C1-4 alkoxy, such as benzyloxy,phenylethoxy, phenylpropoxy, etc., or substituted phenyl C1-4 alkoxy; interms of the substituted phenoxy or substituted phenyl C1-4 alkoxy, thesubstituted groups are selected from the group consisting of C₁₋₄ alkyl,halo, cyano, nitro, and the substituted groups are one or more, whichcould be the same or different groups; optionally, the groups aresubstituted in 2, 3, 4, 5 or 6-position of the benzene ring, for example4-nitrobenzyloxyl, 2-chloro-4-nitrobenzyloxyl; amino and benzylamino.

R1 is C₁₋₄ alkyl or hydrogen; the described C₁₋₄ alkyl is selected frommethyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl;preferably, R1 is hydrogen or methyl.

Optionally, in the above-mentioned method for synthesizing the compoundof Formula (I) provided by the invention, the step (2) is: when A and Bare both C₁₋₁₀ alkoxy, aryloxy, or arylC₁₋₄alkoxy, the compound ofFormula (IV) is ammonolyzed to yield the monoamide compound of Formula(IV′), and then the monoamide compound of Formula (IV′) is cyclized inalkaline condition (such as in the presence of inorganic base, forexample potassium carbonate, sodium carbonate, etc., or organic base,for example potassium tert-butoxide or sodium methoxide, etc.), to yieldthe compound of Formula (I); the monoamide compound of Formula (IV′) mayalternatively continue to be ammonolysed to yield eventually diamide ofFormula (IV″), and then diamide of Formula (IV″) is heated to becyclized in or out of the presence of formamide or methanesulfonic acid,to yield the compound of Formula (I);

wherein, each other substituted group in the Formula (IV), (IV′), (IV″)and (I) is defined as above.

Optionally, in the above-mentioned method for synthesizing the compoundof Formula (I) provided by the invention, the step (2) is: when A and Bare both C₁₋₁₀ alkoxy, aryloxy, or arylC₁₋₄ alkoxy, the compound ofFormula (IV) is hydrolyzed to yield the monoamide compound of Formula(V);

after yielding the compound of Formula (V), the compound of Formula (V)is further cyclized (such as in the condition of acid anhydride andheating) to yield the compound of Formula (VI);

after yielding the compound of Formula (VI), the compound of Formula(VI) is further ring-opening ammonolyzed to yield the compound ofFormula (VII); then the compound of Formula (VII) reacts in the presenceof condensing agent (such as thionylchloride, dicyclohexylcarbodiimide(DCC), phosphorus oxychloride, carbonyldiimidazole, etc.), to yield thecompound of Formula (I):

wherein, each other substituted group in the Formula (IV), (V), (VI) and(VII) is defined as above.

More preferably, the present invention provides a method for preparing3-(substituted dihydroisoindolinone-2-yl)-2,6-dioxopiperidine, i.e. thecompound of Formula (I), including:

wherein: in the formula (I),

substituted group R is amino, nitro or halo (such as F, Cl, Br or I);R3, R4 and R5 are all hydrogen;

Y is ═O; Z is H;

R1 is hydrogen or methyl;

(1) the following compound of Formula (II) is stirred in the presence ofpotassium hydroxide, potassium carbonate, sodium hydroxide, sodiumcarbonate, cesium hydroxide or cesium carbonate for 5 minutes˜6 hours;preferably, in the presence of potassium hydroxide, potassium carbonate,cesium hydroxide or cesium carbonate, and more preferably in thepresence of cesium hydroxide or cesium carbonate; the reaction time ispreferably 10 minutes˜4 hours, and more preferably 20 minutes˜4 hours;then the corresponding compound of Formula (III) is added into thereaction system to react with stirring, the reaction temperature is −20°C.˜80° C.; the reaction temperature is preferably 0° C.˜50° C., and morepreferably 10° C.˜30° C.; the reaction time is 1 hour˜72 hours,preferably 8 hours˜48 hours, and more preferably 12 hours˜28 hours; thecorresponding compound of Formula (IV) is yielded in the reaction. inthese conditions:

Formula sequence Compound of Compound of Compound of number Formula (II)Formula (III) Formula (IV) 1

2

3

4

(2) the compound of Formula (IV) in step (1) is cyclized in the presenceof alkali metal amide (such as lithium amide, sodium amide, potassamide,preferred sodium amide); the reaction temperature is −60° C.˜80° C.,preferably −40° C.˜50° C., and more preferably −30° C.˜20° C.; thereaction time is 30 minutes˜24 hours, preferably 1 hour˜12 hours, andmore preferably 2 hours˜8 hours; the corresponding compounds of Formula(I) are yielded in the reaction; alternatively, the compound of Formula(IV) in step (1) is cyclized in the presence of urea; the reactiontemperature is 50˜250° C. preferably 100˜200° C., and more preferably130˜160° C.; the reaction time is 30 minutes˜24 hours, preferably 1hour˜12 hours, and more preferably 2 hours˜8 hours; the correspondingcompounds of Formula (I) are yielded in the reaction;

in these conditions:

Formula sequence Compound of Compound of number Formula (IV) conditionsFormula (I) 1

NaNH₂ or KNH₂

2

NH₂CONH₂

3

NaNH₂ or KNH₂

4

NH₂CONH₂

5

NaNH₂ or KNH₂

6

NH₂CONH₂

7

NH₂CONH₂

alternatively, the compound of Formula (IV) in step (1) is ammonolyzedin alkaline condition to yield the monoamide compounds of Formula (IV′);then the monoamide compound of Formula (IV′) is cyclized in thecondition of alkali such as potassium tert-butoxide, potassium carbonateetc. to yield the compound of Formula (I); alternatively the monoamidecompound of Formula (IV′) continues to be ammonolyzed to yield diamidecompound of Formula (IV″), and then the compound of Formula (IV″) isheated to be cyclized to yield the compound of Formula (I);

in particular, preferred ammonolysis conditions are: the compound ofFormula (IV) is added into a single organic solvent or mixture of two ormore organic solvents containing saturated ammonia such as ammoniawater, ammonia/methanol, ammonia/tetrahydrofuran, ammonia/dioxane orammonia/dimethylformamide; preferably ammonia/methanol orammonia/tetrahydrofuran; the reaction temperature is between −20° C. andthe refluxing temperature, preferably −10° C.˜40° C., and morepreferably 0° C.˜20° C.; the reaction time for preparing the compound ofFormula (IV′) is 10 minutes˜18 hours, preferably 2 hours˜12 hours, morepreferably 3 hours˜8 hours; the synthesis time of the compound ofFormula (IV″) is 6 hours˜72 hours, preferably 8 hours˜32 hours, morepreferably 10 hours˜24 hours;

optional reaction conditions of cyclization of the compound of Formula(IV′) are: in the presence of alkali, by cyclization the compound ofFormula (I) is yielded. In particular, when metal organic base such aspotassium tert-butoxide or sodium tert-butoxide is selected, reactiontemperature is between −20° C. and the refluxing temperature, preferably−10° C.˜50° C., and more preferably 0° C.˜20° C.; reaction time is 10minutes˜48 hours, preferably 20 minutes˜24 hours, Z) more preferably 30minutes˜6 hours. When inorganic base such as potassium carbonate orsodium carbonate is selected, reaction solvent can be acetonitrile ortetrahydrofuran, and reaction temperature can be between 30° C. and therefluxing temperature;

in these condition:

se- Formula quence Compound of Compound of Compound of number Formula(IV) Formula (IV′) Formula (I) 1

2

3

4

optional reaction conditions of synthesis of the compound of formula (I)by cyclization of the compound of Formula (IV″) are: in or out of thepresence of formamide or methanesulfonic acid, by heated cyclization thecompound of Formula (I) is yielded. In particular, the optional reactiontemperature is 0° C.˜250° C., preferably 60° C.˜200° C. and morepreferably 120° C.˜18000; the reaction time is 10 minutes˜12 hours,preferably 1 hour˜10 hours, more preferably 2 hours˜8 hours;

in these conditions:

Formula sequence Compound of Compound of Compound of number Formula (IV)Formula (IV″) Formula (I) 1

2

3

4

alternatively, the compound of Formula (IV) in the step (1) ishydrolyzed to yield the compound of Formula (V), and the reactionconditions in particular are: the compound of Formula (IV) is posed in amixture system of organic solvent (the solvent is selected fromacetonitrile, tetrahydrofuran, dioxane, methyl tert-butyl ether,dichloromethane, etc., preferably, a single solvent or mixture of two ormore solvents of acetonitrile, tetrahydrofuran, dioxane) and water inany optional ratio; in the alkali system of potassium carbonate, sodiumcarbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide,at certain temperature, by stirred reaction the compound of Formula (V)is yielded, in which alkaline condition is preferably lithium hydroxide,sodium hydroxide, sodium carbonate or potassium carbonate, and morepreferably potassium carbonate or sodium carbonate. To yield thecompound of Formula (V), the reaction temperature can be between −20° C.and the refluxing temperature, preferably between room temperature andthe refluxing temperature, and more preferably 30° C.˜50° C.; thereaction time is 30 minutes˜24 hours, preferably 8 hours˜24 hours, morepreferably 12 hours˜18 hours;

in these conditions:

sequence Formula number Compound of Formula (IV) Compound of Formula (V)1

2

3

4

after that, the obtained compound of Formula (V) is cyclized to yieldthe compound of Formula (VI), and the specific reaction procedure is: indry surrounding a mixture of the compound of Formula (V), aceticanhydride and catalytic amount of pyridine is stirred by heating up andthen the reactant is concentrated to dryness to yield the compound ofFormula (VI), wherein: to yield the compound of Formula (VI), thereaction temperature is between room temperature and 120° C., preferablybetween 40° C.˜100° C. and more preferably 5° C.˜80° C.; the reactiontime, in particular, is 1 minute˜12 hours, preferably 10 minutes˜6hours, more preferably 20 minutes˜4 hours;

in these conditions:

sequence Formula number Compound of Formula (V) Compound of Formula (VI)1

2

3

4

subsequently, the compound of Formula (VI) undergoes ring-openingammonolysis to yield the compound of Formula (VII) which is thencyclized in the presence of condensing agent (such as thionyl chloride,dicyclohexylcarbodiimide (DCC), phosphorus oxychloride,carbonyldiimidazole, etc.), to yield the compound of Formula (I). Inparticular, the procedure of synthesis of the compound of Formula (VII)from the compound of Formula (VI) is: in dry surrounding, the compoundof Formula (IV) is added into supersaturated solution ofammonia/methanol, ammonia/tetrahydrofuran, ammonia/dioxane orammonia/dimethylformamide; the above ammonia organic solvent system canbe a single organic solvent or mixture of two or more organic solventsof methanol, tetrahydrofuran, dioxane or dimethylformamide. To yield thecompound of Formula (VII), stirred reaction temperature is −40° C.˜80°C., preferably −20° C.˜50° C. and more preferably −10° C.˜30° C.; thereaction time is 5 minutes˜24 hours, preferably 30 minutes˜12 hours,more preferably 1 hours˜6 hours. In dry condition and in the reactionsystem of dimethylformamide, dimethylacetamide and halogenatedhydrocarbon, thionyl chloride is added drop by drop into the compound ofFormula (VII) to yield the compound of Formula (I), in which thereaction temperature is −40° C.˜80° C., preferably −30° C.˜40° C. andpreferably −20° C.˜20° C.; the reaction time is 10 minutes˜24 hours,preferably 30 minutes˜6 hours, more preferably 30 minutes˜3 hours;

in these conditions:

Formula sequence Compound of Compound of Compound of number Formula (VI)Formula (VII) Formula (I) 1

2

3

4

The reaction routes of the reaction process mentioned above aredescribed in diagram A:

The reaction routes of the reaction process mentioned above aredescribed in diagram B:

The reaction routes of the reaction process mentioned above aredescribed in diagram C:

In another aspection of the invention, the following intermediatecompounds of Formula (IV) are provided:

wherein:

One of R, R3, R4 and R5 is amino or protected amino (carbamates: such ascarbobenzyloxy, t-butyloxycarbonyl, fluorenylmethoxycarbonyl, etc.; acylamide: such as acetyl, phenylacetyl, phthalyl, etc.; azanes: such asallyl, etc.; sulfonyl and sulfinyl: such as phenylsulfonyl,p-toluenesulfonyl, phenylsulfinyl, O-nitrophenylsulfinyl, etc.; referredto T. W. and WuTs P. G. M. Protective Groups in Organic Synthesis:P494-; East China University Of Science And Technology Press), nitro orhalo (for example F, Cl, Br or I), and the others are hydrogen.preferably, R3, R4 and R5 are hydrogen;

X is halo, such as: F, Cl, Br or I;

Y is ═O or H;

Z is ═O or H;

and with the proviso that Y and Z are both ═O; or one of Y and Z is ═Oand the other of Y and Z is H;

A and B are each independently hydroxyl, C₁₋₁₀ alkoxy, aryloxy, arylC₁₋₄ alkoxy or NHR₂, in which R₂ is hydrogen or amino protecting group(carbamates: such as carbobenzyloxy, t-butyloxycarbonyl,fluorenylmethoxycarbonyl, etc.; acyl amides: such as acetyl,phenylacetyl, phthalyl, etc.; azanes: such as allyl, etc.; sulfonyl andsulfinyl: such as phenylsulfonyl, p-toluenesulfonyl, phenylsulfinyl,O-nitrophenylsulfinyl, etc.; referred to Protective Groups in OrganicSynthesis: Greene T. W., WuTs P. G. M. East China University Of ScienceAnd Technology Press: P494-); preferably, A and B are each independentlyhydroxyl, methoxy, ethoxyl, propoxy, isopropoxy, butoxy, isobutoxy,t-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy;phenoxy or substituted phenoxy; phenyl C1-4 alkoxy, such as benzyloxy,phenylethoxy, phenylpropoxy, etc., or substituted phenyl C1-4 alkoxy; interms of the substituted phenoxy or substituted phenyl C1-4 alkoxy, thesubstituted groups are selected from the group consisting of C₁₋₄ alkyl,halo, cyano, nitro, and the substituted groups are one or more, whichcould be the same or different groups; optionally, the groups aresubstituted in 2, 3, 4, 5 or 6-position of the benzene ring, for example4-nitrobenzyloxyl, 2-chlorine-4-nitrobenzyloxyl; amino and benzylamino;

R1 is C₁₋₄ alkyl or hydrogen; the described C₁₋₄ alkyl is selected frommethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl; preferably,R1 is hydrogen or methyl;

and with proviso that the following compounds are not included: when Ris nitro, A and B are both methoxy, benzyloxy, hydroxyl or amino; when Ris nitro, A is methoxy and B is amino; when R is amino, A and B are bothethoxyl; when R is nitro, A is amino and B is alkoxide.

Preferably, the present invention provides the compounds of Formula(IV′):

the definitions of the substituted groups in the compounds of Formula(V′) are identical to that in the compounds of Formula (IV); morepreferably, one of Y and Z is ═O, and the other is H.

Preferably, the present invention provides the compounds of Formula(IV″):

the definitions of the substituted groups in the compounds of Formula(IV″) are identical to that in the compounds of Formula (IV); morepreferably, one of Y and Z is ═O, and the other is H.

Preferably, the present invention provides the compound of Formula (V):

wherein: the definitions of the substituted groups in the compound ofFormula (V) are identical to that in the compound of Formula (IV); morepreferably, one of Y and Z is ═O, and the other is H; and with theproviso that the following compounds are not included: when R is aminoor nitro, R1, R3, R4 and R5 are all hydrogen, and Y is ═O, and Z is ═Oor H.

Preferably, the present invention provides the compounds of Formula(VI):

wherein: the definitions of the substituted groups in the compounds ofFormula (VI) are identical to that in the compounds of Formula (IV);more preferably, one of Y and Z is ═O, and the other is H; and with theproviso that the following compounds are not included: when R is nitro,R1, R3, R4 and R5 are all hydrogen, and Y is ═O, and Z is ═O.

Preferably, the present invention provides the compounds of Formula(VII):

wherein: the definitions of the substituted groups in the compounds ofFormula (VII) are identical to that in the compounds of Formula (IV);more preferably, one of Y and Z is ═O, and the other is H; and with theproviso that the following compounds are not included: when R is aminoor nitro, R1, R3, R4 and R5 are all hydrogen, Y is ═O, and Z is ═O or H.

Further preferably, the present invention provides the compounds offollowing formula:

By comparison with the existing synthesis routes, the present inventionhas the following advantages:

1. The raw materials used in the present invention are accessible,whereas the raw materials used in original R&D Corporation's route arecommercially unavailable internally:

Initial materials: α-aminoglutarimide hydrochloride is commerciallyunavailable internally. It is synthesized fromN-benzyloxycarbony-L-glutamine, which reacts withN,N′-carbonyldiimidazole in THF refluxing to yieldN-benzyloxycarbony-aminoglutarimide. After that amino protection groupis removed and α-aminoglutarimide hydrochloride is yielded byhydrogenation under certain pressure catalyzed with Pd/C.

Key materials in reaction: methyl 2-bromomethyl-3-nitrobenzoate issynthesized from 2-methyl-3-nitrobenzoate, which is brominated byrefluxing over 24 h in the presence of lethal carbon tetrachloride andin the condition of ultraviolet light photocatalysis under mercury lamp.Photocatalytic reaction has low yield and the difficulty in massproduction, as well as the difficulty in labour protection againstultraviolet light emitted by the catalytic light source—mercury lamp.

2. Comparison of time length and degree of difficulty of reaction, yieldpurity, as well as degree of extraction and purification:

In both the US Patent application US2006052609A1 and the Chinese Patentapplication CN97180299.8, the reaction product was purified by columnchromatography at least twice or more, which made industrial operationcomplicated and made it difficult to industrial scale-up production.

In both the US Patent application US2006052609A1 and the Chinese Patentapplication CN97180299.8, pressurized hydrogenation was utilized twice;In the present invention, only Pd/C and ammonium formate are used indeprotection reduction, which is of high security and mild conditions.By comparison with hydrogenation under certain pressure, hydrogenationunder atmospheric pressure is of less risk, leading to enhancedproduction security.

When N-benzyloxycarbony-L-glutamine, as initial material, reacted withN,N′-carbonyldiimidazole in THF refluxing for 24 h to yieldN-benzyloxycarbony-aminoglutarimide, low purity of yield results fromlong reactive time and high temperature.

3. Comparison of yield in each procedure and total yield:

The total yield was lower than 20% and 18% respectively reported in theUS Patent application US2006052609A1 and the Chinese Patent application.

In the present invention, the total yield of3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidinesynthesized from the original raw material,4-nitro-2,3-dihydro-1H-isoindol-1-one and α-bromodimethyl glutarate,averages from 35% to 40%, due to the short reaction routes and simplemethods.

4. Toxicity of solvent and its influence on environment:

In the US Patent application US2006052609A1 and the Chinese Patentapplication, carbon tetrachloride was reported to be reaction solventused for refluxing, which did extreme harm to environment and madeinnocent treatment and labor protection difficult.

In the present invention, derivatives of benzene or carbon tetrachlorideare unavailable to be as reaction solvent, which is relativelyeco-friendly.

DESCRIPTION OF EMBODIMENTS

The following examples will serve to further elaborate the presentinvention seeing the above routes A, B and C, which shouldn't beunderstood as a limitation in the scope of this invention by the personskilled in the art. Any modification or improvement based on theinstruction well known in the art should be in the scope of thisinvention, without departing from the spirit and scope of the presentinvention.

Example 1 The synthesis of 4-nitro-2,3-dihydro-1H-isoindol-1-one

A mixture of methyl 2-bromomethyl-3-nitrobenzoate (20 g) and methanol(200 ml) was stirred under ammonia gas for 30 min at room temperature,and was kept in heat preservation for 2 hours. Crystal grew in an icebath for 2 hours, and then filtered, and dried to give 11.7 g of lightyellow crystal. yield: 90%. mp: 235.4˜236.7° C.

¹H-NMR: (300 MHz, DMSO-d₆) δ: 4.78 (s, 2H), 7.79 (t, 1H), 8.10 (d, 1H),8.41 (d, 1H), 8.90 (S, 1H).

¹H-NMR: (300 MHz, DMSO-d₆/D₂O) δ: 4.76 (s, 2H), 7.77 (t, 1H), 8.08 (d,1H), 8.39 (d, 1H).

FAB(M+1): 179

Element analysis:

theoretical data: C, 53.94%; H, 3.39%; N, 15.72%.

measured data: C, 54.08%; H, 3.49%; N, 15.81%.

Test condition of HPLC:

-   -   type and specification of column: phenomenex Luna 5u C18 250        mm×4.6 mm; velocity: 1.0 ml/min; λ=230 nm        -   mobile phase: acetonitrile/0.1% phosphate=30/70        -   appearance time of target yield: 5.810 minutes        -   purity of target yield: 99.59%

Example 2 The synthesis of 4-amino-2,3-dihydro-1H-isoindol-1-one

A mixture of 4-nitro-2,3-dihydro-1H-isoindol-1-one (20 g), ammoniumformate (35 g) and 7.5% Pd/C (0.6 g) in methanol (60 ml) was stirred for2 hours by heating up to 35° C. Pd/C was filtered and the filtrateconcentrated under reduced pressure. The residue was recrystallized fromwater to give 15.3 g. of light yellow solid. yield: 92%. mp: 195.6-197°C.

¹H-NMR: (300 MHz, DMSO-d₆) δ: 4.31 (s, 2H), 6.76 (d, 1H), 7.14 (t, 1H),6.86 (d, 1H), 5.30 (s, 2H), 8.26 (s, 1H)

¹H-NMR: (300 MHz, DMSO-d₆/D₂O) δ: 4.14 (s, 2H), 6.79 (d, 1H), 6.93 (d,1H), 7.16 (t, 1H)

FAB(M+1): 149

Element analysis: theoretical data: C, 64.85%; H, 5.44%; N, 18.91%.

measured data: C, 64.96%; H, 5.61%; N, 19.02%.

Test condition of HPLC:

-   -   type and specification of column: phenomenex Luna 5u C18 250        mm×4.6 mm; velocity: 1.0 ml/min; k=230 nm        -   mobile phase: acetonitrile/0.1% phosphate=15/85 or            acetonitrile/0.01M ammonium acetate=10/90        -   appearance time of target yield: 3.580 minutes; 4.790            minutes        -   purity of target yield: 99.66%

Example 3 The Synthesis of α-Bromodimethyl Glutarate

In a dry reaction flask, thionyl chloride 36 ml was added into a stirredmixture of glutaric acid (30 g) and chloroform (90 ml) under reflux for2 hours, and then bromine (36 g) was added under reflux for over 16hours. The reaction mixture was cooled, into which methanol (75 ml) wasthen added by droplet in an ice bath and stirred in heat preservationfor 2 hours. The resulting mixture was washed with 5% sodium bisulfate(150 ml), saturated sodium bicarbonate (150 ml) and saturated sodiumchloride (150 ml) one by one. The organic layer was dried with anhydroussodium sulfate and after that sodium sulfate was removed by filter. Thefiltrate was concentrated to dryness and distilled under reducedpressure, to collect the fraction at 110-115° C./5 mmHg. The targetyield is colorless liquid. weight: 41.3 g. yield: 76%.

FAB(M+1): 240

Test condition of HPLC:

-   -   type and specification of column: phenomenex Luna 5u C18 250        mm×4.6 mm; velocity: 1.0 ml/min; λ=230 nm        -   mobile phase: acetonitrile/0.1% phosphate=50/50        -   appearance time of target yield: 7.750 minutes        -   purity of target yield: 96.64%

Example 4 The synthesis of dimethyl3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutarate

A mixture of 4-amino-2,3-dihydro-1H-isoindol-1-one (5 g),N-methylpyrrolidone (25 ml), cesium carbonate (11 g) and α-bromodimethylglutarate (9.7 g) was stirred under nitrogen at room temperature overnight. After adding water (75 ml) and methylene chloride (50 ml), removethe aqueous phase and the organic phase was extracted with 2 mol/Lhydrochloric acid. The aqueous hydrochloric acid solution was mixed withmethylene chloride (100 ml) and phases separated at pH7 adjusted byaddition of Na₂CO₃. The organic phase was dried over anhydrous sodiumsulfate and concentrated under reduced pressure to give a yellow tickingsubstance (7.2 g) which could be used in next reaction without furtherpurification. yield: 70%

¹H-NMR: (300 MHz, DMSO-d₆) δ: 2.19 (m, 2H), 2.35 (t, 2H), 3.52 (s, 3H),3.66 (s, 3H), 4.23 (s, 2H), 4.90 (m, 1H), 5.38 (s, 2H), 6.79 (d, 1H),6.89 (d, 1H), 7.17 (t, 1H).

¹H-NMR: (300 MHz, DMSO-d₆/D₂O) δ: 2.10 (m, 2H), 2.33 (t, 2H), 3.53 (s,3H), 3.66 (s, 3H), 4.22 (s, 2H), 4.90 (m, 1H), 5.38 (s, 2H), 6.80 (d,1H), 6.89 (d, 1H), 7.17 (t, 1H).

FAB(M+1): 307

Element analysis: theoretical data: C, 58.82%; H, 5.92%; N, 9.15%.

measured data: C, 58.74%; H, 6.06%; N, 9.06%.

Test condition of HPLC:

-   -   type and specification of column: phenomenex Luna 5u C18 250        mm×4.6 mm; velocity: 1.0 ml/min; λ=230 nm        -   mobile phase: acetonitrile/0.1% phosphate=30/70        -   appearance time of target yield: 7.620 minutes        -   purity of target yield: 92.1%            With the similar methods, the compounds in the following            table are obtained:

Formula original yield/purity sequence raw starting (HPLC by numbermaterial material target yield normalization) 1

yield: 68.3% purity: 93.5% 2

yield: 73.7% purity: 91.4% 3

yield: 59.3% purity: 89.1%

Example 5 The synthesis of3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine

Under nitrogen in dry reaction flask was added sodium amide (30 mmol1.17 g) (obtained by adding metallic sodium (690 mg) into liquid ammonia(−40° C., 300 ml) and then adding catalytic amount of ferric nitrate).The solution of dimethyl3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutarate (3 g, 10 mmol)in anhydrous tetrahydrofuran (100 ml) was added by droplet with thetemperature maintaining at −40° C. and the mixture was stirred in heatpreservation for 3 hours. ammonium chloride (5 g) (ammonia spillover isallowed) and water (300 ml) were added and the resulting mixture wasfiltered. The crude was recrystallized from isopropanol (15 ml) to givetarget yield (1.22 g).

Yield 48%. mp: 251.5° C.˜252.5° C.

¹H-NMR: (500 MHz, DMSO-d₆) δ: 2.02˜2.04 (m, 1H), 2.27˜2.34 (m, 1H),2.60˜2.63 (m, 1H), 2.88˜2.95 (m, 1H), 4.16 (dd, 2H), 5.10 (dd, 2H), 6.80(d, 1H), 6.92 (d, 1H), 7.19 (t, 1H), 10.19 (s, 1H) FAB(M+1): 260

Element analysis: theoretical data: C, 60.22%; H, 5.05%; N, 16.21%.

measured data: C, 60.14%; H, 5.16%; N, 16.30%.

Test condition of HPLC:

-   -   type and specification of column: phenomenex Luna 5u C18 250        mm×4.6 mm; velocity: 1.0 ml/min; λ=230 nm        -   mobile phase: acetonitrile/0.1% phosphate=10/90        -   appearance time of target yield: 11.81 minutes        -   purity of target yield: 99.29%            With the similar methods, the compounds in the following            table are obtained:

Formula yield/purity sequence starting (HPLC by number material targetyield normalization) 1

yield: 53% purity: 93.23% 2

yield: 39.7% purity: 94.77%

Example 6 The synthesis of methylN-[4-amin-1-oxo-1,3-dihydro-2H-isoindol-2-yl]-glutaminate

A mixture of dimethyl3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutarate (30.6 g),saturated dioxane/ammonia solution (150 ml) and lipase (14 g) wasstirred at 20° C. for 3˜5 hours. The reaction mixture concentrated byreduced pressure at room temperature to remove ammonia and thenconcentrated under reduced pressure to dryness. The concentrate wasstirred with methyl tert-butyl ether (100 ml) and then white crystal wasprecipitated. After filter the residue was dried under vacuum at roomtemperature to give 21.4 g of target yield as a white crystal. yield:73%. mp: 103-106° C.

¹H-NMR: (300 MHz, DMSO-d₆) δ: 4.17 (d, 1H), 4.40 (d, 1H), 5.43 (s, 2H),6.76 (d, 1H), 7.17 (t, 1H), 6.87 (d, 1H), 4.73 (m, 1H), 1.91 (m, 2H),2.18 (t, 2H), 3.51 (s, 3H), 7.13 (s, 1H), 7.55 (s, 1H).

¹H-NMR: (300 MHz, DMSO-d₆/D2O) δ: 4.17 (d, 1H), 4.40 (d, 1H), 6.76 (d,1H), 7.17 (t, 1H), 6.87 (d, 1H), 4.73 (m, 1H), 1.91 (m, 2H), 2.18 (t,2H), 3.51 (s, 3H).

FAB(M+1): 292

Test condition of HPLC:

-   -   type and specification of column: phenomenex Luna 5u C18 250        mm×4.6 mm; velocity: 1.0 ml/min; λ=230 nm        -   mobile phase: acetonitrile/0.1% phosphate=10/90        -   appearance time of target yield: 19.900 minutes        -   purity of target yield: 98.3%            With the similar methods, the compounds in the following            table are obtained:

Formula yield/purity sequence starting (HPLC by number material targetyield normalization) 1

yield: 72% purity: 97.96% 2

yield: 75.1% purity: 97.55% 3

yield: 64.1% purity: 96.74%

Example 7 The synthesis3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-dioxopiperidine

A mixture of methylN-[4-amin-1-oxo-1,3-dihydro-2-hydro-isoindol-2-yl]-glutaminate (20 g) inacetonitrile (300 ml) was stirred with potassium carbonate (9.4 g) underreflux for 5 hours. The reaction mixture was concentrated to removeacetonitrile and was stirred with ethyl acetate (100 ml) and water (50ml). After filter, recrystallization from isopropanol gave a lightyellow solid (14.9 g). yield: 84%. mp: 250.5-251.7° C.

¹H-NMR: (300 MHz, DMSO-d₆) δ: 2.03˜2.06 (m, 1H), 2.26˜2.34 (m, 1H),2.59˜2.63 (m, 1H), 2.85˜2.92 (m, 1H), 4.15 (dd, 2H), 5.09 (dd, 2H), 6.81(d, 1H), 6.92 (d, 1H), 7.20 (t, 1H), 10.18 (s, 1H).

FAB(M+1): 260

Element analysis: theoretical data: C, 60.22%; H, 5.05%; N, 16.21%.

measured data: C, 60.12%; H, 5.17%; N, 16.29%.

Test condition of HPLC:

-   -   type and specification of column: phenomenex Luna 5u C18 250        mm×4.6 mm; velocity: 1.0 ml/min; λ=230 nm        -   mobile phase: acetonitrile/0.1% phosphate=10/90        -   appearance time of target yield: 11.73 minutes        -   purity of target yield: 99.61%            With the similar methods, the compounds in the following            table are obtained:

Formula yield/purity sequence starting (HPLC by number material targetyield normalization) 1

yield: 81% purity: 98.61% 2

yield: 86% purity: 99.21% 3

yield: 71% purity: 97.97%

Example 8 The synthesis of3-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]-glutaramide

A mixture of dimethyl3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutarate (30.6 g),anhydrous acetonitrile (150 ml) and triethylamine (13.9 ml) was stirredwith benzyl chloroformate (17.1 g) under catalytic amount of MAP underreflux for 4 hours. The reaction mixture was cooled to room temperatureand then mixed with water (500 ml). The resulting mixture was thenextracted with dichloromethane and dried over anhydrous sodium sulphate,then concentrated under reduced pressure to give a red sticky substance(66 g). The solution of residue in supersaturated methanol-ammonia (250ml) was stirred at 25˜30° C. for over 24 hours and white solid wasprecipitated. Crystal grew in an ice bath for 2 hours. After filter thecake was dried under reduced pressure to give 44.4 g of white crystal.yield: 67%. mp: 190˜192° C.

¹H-NMR: (300 MHz, DMSO-d₆) δ: 4.29 (d, 1H); 4.56 (d, 1H), 7.56 (s, 1H),6.59 (d, 1H), 7.34 (t, 1H), 6.88 (d, 1H), 4.70 (m, 1H), 2.01 (m, 2H),2.20 (m, 1H), 2.02 (m, 1H), 6.59 (s, 1H); 6.74 (s, 1H), 4.38 (s, 2H),7.14˜7.40 (m, 7H).

¹H-NMR: (300 MHz, DMSO-d₆/D₂O) δ: 4.29 (d, 1H); 4.56 (d, 1H), 6.59 (d,1H), 7.34 (t, 1H), 6.88 (d, 1H), 4.70 (m, 1H), 2.01 (m, 2H), 2.20 (m,1H), 2.02 (m, 1H), 4.38 (s, 2H), 7.14˜7.40 (m, 5H).

FAB(M+1): 443

Test condition of HPLC:

-   -   type and specification of column: phenomenex Luna 5u C18 250        mm×4.6 mm; velocity: 1.0 ml/min; λ=230 nm        -   mobile phase: acetonitrile/0.1% phosphate=40/60        -   appearance time of target yield: 6.980 minutes        -   purity of target yield: 98.67%            With the similar methods, the compounds in the following            table are obtained:

Formula yield/purity sequence starting (HPLC by number material targetyield normalization) 1

yield: 72% purity: 97.96% 2

yield: 75.1% purity: 97.55% 3

yield: 64.1% purity: 96.74%

Example 9 The synthesis of3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-dioxopiperidine

3-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]-glutaramide(30 g) was stirred with formamide (150 ml) for 3˜4 hours by slowlyheating up to 160° C. The reaction mixture was cooled to 0° C. and thenmixed with water (750 ml). After crystal growing for 1 hour, theresulting mixture was filtered and dried to give 21.6 g of light yellowsolid. The solution of this residue in methanol (325 ml) was stirredwith 5% Pd/C (0.3 g) and formamide (22 g) at 30° C. for 2 hours. Pd/Cwas filtered and the filtrate concentrated under reduced pressure toyield a yellow solid. Recrystallization and washing by isopropanol andactive carbon gave 12.75 g of light yellow solid. yield: 72%. mp:251.1˜252.4° C.

¹H-NMR: (300 MHz, DMSO-d₆) δ: 2.02 (m, 2H), 2.01˜2.06 (m, 1H), 2.25˜2.39(m, 1H), 2.59˜2.64 (m, 1H), 2.83˜2.94 (m, 1H), 4.16 (dd, 2H), 5.08 (dd,1H), 5.35 (s, 2H), 6.80 (d, 1H), 6.93 (d, 1H), 7.90 (t, 1H), 10.91 (s,1H).

FAB(M+1): 260

Element analysis: theoretical data: C, 60.22%; H, 5.05%; N, 16.21%.

measured data: C, 60.27%; H, 5.13%; N, 16.26%.

Test condition of HPLC:

-   -   type and specification of column: phenomenex Luna 5u C18 250        mm×4.6 mm; velocity: 1.0 ml/min; λ=230 nm        -   mobile phase: acetonitrile/0.1% phosphate=10/90        -   appearance time of target yield: 11.77 minutes        -   purity of target yield: 99.37%            With the similar methods, the compounds in the following            table are obtained:

Formula yield/purity sequence starting (HPLC by number material targetyield normalization) 1

yield: 83% purity: 98.97% 2

yield: 81% purity: 99.03% 3

yield: 76% purity: 98.63%

Example 10 The synthesis of3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutaric acid

A mixture of dimethyl3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutarate (5 g) andtetrahydrofuran (14 ml) in 20% potassium carbonate solution (45 ml) wasstirred for 5 hours by heating up to 50° C. The aqueous phase wasseparated and concentrated to dryness under reduced pressure. Theconcentrate was stirred with methanol (50 ml) for 30 min. After filter,the filtrate concentrated to dryness and was mixed with isopropanol (50ml) for crystal growing for 2 hours at room temperature. The resultingmixture was filtered and dried under reduced pressure to give 3.7 g oftarget yield as a white solid. yield: 81%. Melting point test showedthat the product began to melt at 90° C. and the final melting point wasnot apparently observed.

¹H-NMR: (300 MHz, DMSO-d₆) δ: 2.01 (m, 2H), 2.20 (m, 2H), 3.78 (m, 1H),4.55 (s, 2H), 5.30 (s, 2H), 6.73 (d, 1H), 6.85 (d, 1H), 7.12 (t, 1H),10.99 (br, 2H).

¹H-NMR: (300 MHz, DMSO-d₆/D₂O) δ: 1.88 (m, 2H), 2.09 (m, 2H), 3.71 (m,1H), 4.49 (s, 2H), 6.76 (d, 1H), 6.90 (d, 1H), 7.15 (t, 1H).

FAB(M+1): 279

Element analysis: theoretical data: C, 56.11%; H, 5.07%; N, 10.07%.

measured data: C, 56.20%; H, 5.21%; N, 10.18%.

Test condition of HPLC:

-   -   type and specification of column: phenomenex Luna 5u C18 250        mm×4.6 mm; velocity: 1.0 ml/min; λ=230 nm        -   mobile phase: acetonitrile/0.1% phosphate=15/85        -   appearance time of target yield: 5.260 minutes        -   purity of target yield: 98.7%            With the similar methods, the compounds in the following            table are obtained:

Formula yield/purity sequence starting raw (HPLC by number materialmaterial target yield normalization) 1

K₂CO₃/H₂O CH₃OH

yield: 84% purity: 97.9% 2

K₂CO₃/H₂O EtOH

yield: 77% purity: 96.7% 3

K₂CO₃/H₂O EtOH

yield: 68% purity: 93.3%

Example 11 The synthesis3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine

A mixture of 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutaricacid (5 g) and urea (1.08 g) in N, N-dimethylformamide (25 ml) wasstirred and heated under reflux for 3˜4 hours. The reaction mixtureconcentrated under reduced pressure at 60° C. and then was added intoice water by being stirred rapidly. After filter, the cake was washedwith isopropanol. The crude product was recrystallized from isopropanoland active carbon to give 1.4 g of off-white target compound. Yield:30%. mp: 252.1˜254.3° C.

¹H-NMR: (300 MHz, DMSO-d₆) δ: 2.03 (m, 2H), 2.01˜2.07 (m, 1H), 2.26˜2.37(m, 1H), 2.61˜2.65 (m, 1H), 2.87˜2.96 (m, 1H), 4.17 (dd, 2H), 5.09 (dd,1H), 5.36 (s, 2H), 6.81 (d, 1H), 6.92 (d, 1H), 7.91 (t, 1H), 10.93 (s,1H).

¹H-NMR: (300 MHz, DMSO-d₆/D₂O) δ: 2.02˜2.05 (m, 1H), 2.32˜2.36 (m, 1H),2.60˜2.65 (m, 1H), 2.83˜2.88 (m, 1H), 4.17 (dd, 2H), 5.04 (dd, 1H), 6.82(d, 1H), 6.94 (d, 1H), 7.20 (t, 1H).

FAB(M+1): 260

Element analysis: theoretical data: C, 60.22%; H, 5.05%; N, 16.21%.

measured data: C, 60.30%; H, 5.20%; N, 16.18%.

With the similar methods, the compounds in the following table areobtained:

Formula yield/purity sequence starting (HPLC by number material targetyield normalization) 1

yield: 33% purity: 99.37% 2

yield: 31% purity: 98.55%

Example 12 The synthesis of3-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]-glutaricanhydride

To a stirred mixture of3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutaric acid (30.6 g)and triethylamine (13.9 ml) in anhydrous acetonitrile (150 ml) was addedbenzyl chloroformate (17.1 g) and catalytic amount of DMAP under refluxfor 4 hours. The resulting mixture was cooled to room temperature andthen added into water (500 ml). The mixture was extracted withdichloromethane and dried over anhydrous sodium sulphate. The resultingmixture was concentrated under reduced pressure to give 66 g of redsticky substance. Then the substance was added in acetic anhydride (250ml) and heated to 50° C., then pyridine (3 ml) was added and reacted at70° C. for 30 minutes. The reaction mixture was dried by reducedpressure and added anhydrous methyl tert-butyl ether. Refinement gave 30g of white target yield. yield: 76%.

FAB(M+1): 395

With the similar methods, the compounds in the following table areobtained:

sequence Formula number starting material target yield yield 1

yield: 91% 2

yield: 87% 3

yield: 85% 4

yield: 90% 5

yield: 93.3%

Example 13 The synthesis of3-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]-isoglutamine

A mixture of3-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]-glutaricanhydride (30 g) in dry tetrahydrofuran (300 ml) was stirred at 0  C.under supersaturated ammonia for 2 hours. After filter, the cake waswashed with ether and dried-under reduced pressure at room temperatureto give 27.3 g of white solid.

yield: 84%. purity: 95.61%.

FAB(M+1): 428

With the similar methods, the compounds in the following table areobtained:

Formula yield/purity sequence starting (HPLC by number material targetyield normalization) 1

yield: 80% purity: 96.1% 2

yield: 78% purity: 94.3% 3

yield: 75% purity: 93.1% 4

yield: 75% purity: 95.3% 5

yield: 79% purity: 94.7%

Example 14 The synthesis of3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine

To a stirred mixture of3-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]-isoglutamine(10 g) in DMF (30 ml) was added thionyl chloride (5 g) by droplet at−20° C. for reaction in heat preservation for 2˜3 hours. The resultingmixture was mixed in ice water stirred rapidly. Then the mixture wasextracted with ethyl acetate (2×50 ml) and dried over anhydrous sodiumsulfate. Sodium sulfate was filtered and the filtrate concentrated todryness under reduced pressure. The concentrate was mixed in methanol(100 ml) and stirred with 5% Pd/C (1 g) and ammonium formate (7 g) at30° C. for 2 hours. Pd/C was filtered and the filtrate concentrated todryness. The concentrate was recrystallized from isopropanol and rinsedwith water. Decompression drying gave 3.76 g of target yield as a lightyellow solid. yield: 62%. mp: 250.8˜252.7° C.

¹H-NMR: (300 MHz, DMSO-d₆/D20) δ: 2.04˜2.10 (m, 1H), 2.34˜2.39 (m, 1H),2.61˜2.67 (m, 1H), 2.87˜2.91 (m, 1H), 4.18 (dd, 2H), 5.08 (dd, 2H), 6.84(d, 1H), 6.96 (d, 1H), 7.23 (t, 1H)

FAB(M+1): 260

Element analysis: theoretical data: C, 60.22%; H, 5.05%; N, 16.21%.

measured data: C, 60.04%; H, 5.31%; N, 16.33%.

Test condition of HPLC:

-   -   type and specification of column: phenomenex Luna 5u C18 250        mm×4.6 mm; velocity: 1.0 ml/min; λ=230 nm        -   mobile phase: acetonitrile/0.1% phosphate=10/90        -   appearance time of target yield: 11.767 minutes        -   purity of target yield: 99.69%.

Example 15 The synthesis of3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine

To a mixture of3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-isoglutamine (9 g) inN,N-dimethylformamide (80 ml), was added thionyl chloride (6.6 g) bydroplet below 0° C. for stirred reaction in heat preservation for 2˜3hours. The resulting solution was added by droplet into mixture of iceand water and pH value was adjusted to 7˜8 with sodium carbonate. Themixture was stirred for 30 minutes and filtered to get light yellowcrude. Refining with methanol gave 6.6 g of target yield as a lightyellow solid. yield: 78%.

FAB(M+1): 290

Element analysis: theoretical data: C, 53.98%; H, 3.83%; N, 14.53%.

measured data: C, 54.06%; H, 3.95%; N, 14.61%.

With the similar methods, the compounds in the following table areobtained:

Formula yield/purity sequence starting (HPLC by number material targetyield normalization) 1

yield: 83% purity: 93.4% 2

yield: 87% purity: 91% 3

yield: 77% purity: 93.1% 4

yield: 81% purity: 92.2%

Example 16 The synthesis of3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine

A mixture of3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-dioxopiperidine (7g), 5% Pd/C (1.4 g) and ammonium formate (2.1 g) in methanol (35 ml) wasstirred completely at room temperature for 2 hours. Pd/C was filteredand the filtrate concentrated to dry under reduced pressure.Recrystallization from heated isopropanol and washing with water gave5.6 g of yellow crystal. yield: 89%. mp: 252.3-254.0° C.

¹H-NMR: (300 MHz, DMSO-d₆) δ: 2.00˜2.08 (m, 1H), 2.27˜2.32 (m, 1H),2.58˜2.64 (m, 1H), 2.86˜2.96 (m, 1H), 4.15 (dd, 2H), 5.11 (dd, 2H), 6.80(d, 1H), 6.91 (d, 1H), 7.19 (t, 1H), 11.00 (s, 1H).

FAB(M+1): 260

Element analysis: theoretical data: C, 60.22%; H, 5.05%; N, 16.21%.

measured data: C, 60.17%; H, 5.21%; N, 16.26%.

Preparation with the same method:

-   (R)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine;

yield: 93%; purity 99.41%.

Preparation with the same method:

-   (S)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine

yield: 91%; purity 99.73%.

Example 17 The synthesis of3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine

A mixture of3-(4-chloro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine (5g) in ammonium formate (30 ml) was stirred by heating up slowly toreflux and then reacted under ammonia for 6˜8 hours. The reactionmixture concentrated to dryness under reduced pressure.Recrystallization from heated isopropanol gave 3.96 g of target yield.yield: 85%. Purity: 99.17%. mp: 251.6˜253.9° C.

¹H-NMR: (300 MHz, DMSO-d₆) δ: 2.05˜2.11 (m, 1H), 2.25˜2.34 (m, 1H),2.60˜2.65 (m, 1H), 2.85˜2.97 (m, 1H), 4.16 (dd, 2H), 5.12 (dd, 2H), 6.82(d, 1H), 6.90 (d, 1H), 7.19 (t, 1H), 10.97 (s, 1H) FAB(M+1): 260

Element analysis: theoretical data: C, 60.22%; H, 5.05%; N, 16.21%.

measured data: C, 60.29%; H, 5.16%; N, 16.27%.

Example 18 The synthesis of3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutaric acid

A mixture of 4-nitro-2,3-dihydro-1H-isoindol-1-one (80 g) and cesiumcarbonate (219 g) in triethylamine (100 ml) was stirred for over half anhour. Under nitrogen ethyl chloroformate (68 ml) was added by dropletbelow 0° C. and reacted by stirring at room temperature for 3˜5 hours.The resulting mixture was added in ice water (1000 mL) and then lightyellow solid was precipitated. After filter, the cake was washed by icedwater. The aqueous phase was extracted with dichloromethane twice andthe combined extracts were dried with anhydrous sodium sulphate. Afterfiltered, the filtrate was concentrated to dry under reduced pressure.The concentrated was diluted with n-hexane (120 ml) and stirred toprecipitate crystal. Filter and drying under reduced pressure gave lightyellow solid.

A mixture of D,L-glutamic acid (66.7 g) in tetrahydrofuran (330 ml) wasstirred with the intermediate prepared above in batches at subzerotemperature. Triethylamine (6.5 ml) was added in the mixture to reactfor 20 min and then for 16˜24 hours under reflux. The reaction mixturewas cooled and filtered. The filtrate was concentrated to dryness underreduced pressure. The concentrate was dissolved in dichloromethane (60ml) and extracted with saturated sodium bicarbonate solution. When pH ofthe resulting mixture was adjusted to 2 by 2N hydrochloric acid, anumber of light yellow solid was precipitated, subsequently extractedwith dichloromethane, and washed with distilled water, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure, finally crystal grew by standing, filtered and dried to give94.2 g of title product as light yellow solid, yield 79%. purity 95.81%.

FAB(M+1): 309.

Element analysis: theoretical data: C, 50.65%; H, 3.92%; N, 9.09%.

measured data: C, 50.54%; H, 4.01%; N, 9.04%.

INDUSTRIAL APPLICABILITY

The present processes have the following advantages:

i. The method for preparing key substrate needed in the synthesis issimple and with low cost, which is suitable for commercial process;

ii. Each step to the present invention is under mild reaction conditionswithout hard long-time reflux.

iii. The products yielded in each step to the present invention are ofhigh purity, which simplify the extraction and purification processwithout column chromatography or other complicated extractionconditions.

iv. There is high yield in each reaction. When3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine issynthesized from the original raw material,4-nitro-2,3-dihydro-1H-isoindol-1-one and α-bromodimethyl glutarate, thetotal yield averages from 35% to 40%. Hence the preparation methods aresimple with low costs.

v. Only by three or four procedures can the key product be yielded,which leads to short synthesis routes and simple methods.

vi. The solvents used in each preparation procedure are easy to bedisposed for environment protection, which is relatively eco-friendly.

1. The following intermediate compounds of Formula (IV):

wherein: One of R, R3, R4 and R5 is amino, protected amino, nitro orhalo, and the others are hydrogen; Y is: ═O or H; Z is: ═O or H; andwith the proviso that Y and Z are both ═O; or one of Y and Z is ═O andthe other of Y and Z is H; A and B are each independently hydroxyl,C₁₋₁₀ alkoxy, aryloxy, aryl C₁₋₄ alkoxy or NHR₂, in which R₂ is hydrogenor amino protecting group; R1 is C₁₋₄ alkyl or hydrogen; and with theproviso that the following compounds are not included: when R is nitro,A and B are both methoxy, benzyloxy, hydroxyl or amino; when R is nitro,A is methoxy and B is amino; when R is amino, A and B are both ethoxyl;when R is nitro, A is amino and B is t-butoxyl.
 2. The compound of claim1 is the following intermediate compounds of Formula (IV′):

the definitions of the substituted groups in the compounds of Formula(IV′) are the same as that in claim
 1. 3. The compound of claim 1 is thefollowing intermediate compounds of Formula (IV″):

the substituted groups in the compounds of Formula (IV″) are as definedin claim
 1. 4. The compound of claim 1 is the following intermediatecompounds of Formula (V):

wherein: the substituted groups in the compounds of Formula (V) are asdefined in claim 1, and with the proviso that the following compoundsare not included: when R is amino or nitro, R1, R3, R4 and R5 are allhydrogen, and Y is ═O, and Z is ═O or H.
 5. The following intermediatecompounds of Formula (VI):

wherein: the substituted groups in the compounds of Formula (VI) are asdefined in claim 1, and with the proviso that the following compoundsare not included: when R is nitro, R1, R3, R4 and R5 are all hydrogen,and Y is ═O, and Z is ═O.
 6. The compound of claim 1 is the followingintermediate compounds of Formula (VII):

wherein: the substituted groups in the compounds of Formula (VII) are asdefined in claim 1, and with the proviso that the following compoundsare not included: when R is amino or nitro, R1, R3, R4 and R5 are allhydrogen, and Y is ═O, and Z is ═O or H.
 7. The compound of claim 1,which is selected from the following intermediate compounds:


8. The compound of claim 5, which is selected from the followingintermediate compounds: